Down Syndrome, due to the triplication of gene products found on human chromosome 21, is a genetic disorder resulting in moderate to profound mental retardation. How Trisomy 21 in the cells of the central nervous system (CMS) alters the maturation and function of the brain, and subsequently, how this aberrant development interferes with cognition in patients with Down syndrome, remains a poorly addressed area of research. It has been previously hypothesized that the neurological state in Down syndrome ensues from developmental instability, manifested non-specifically by the presence of extra genetic material in the human genome, or alternatively, is derived directly from the over-expression of one or a small subset of genes. My preliminary data in Ts65Dn, a well-established mouse model of Down syndrome, in conjunction with previous findings, however, demonstrates that the trisomic condition has an emerging and overriding functional consequence in the CMS: imbalances in the excitability of the brain, which constitutively favor inhibition over excitation in neural circuits, and which undermine normal learning and memory processes. [unreadable] [unreadable] [unreadable]